PROJECT SUMMARY Nearly 10% of Americans practice meditation to improve health. Randomized controlled trials support this practice and show that mindfulness training is effective in improving a broad range of health outcomes. In particular, mindfulness training has been shown to reduce biomarkers of systemic inflammation that contribute to the pathophysiology of disease and predict risk for all-cause mortality. Still, little is known about the biological processes linking mindfulness training with inflammation. This proposal tests the hypothesis that mindfulness training aids the regulation of inflammation by mitigating glucocorticoid resistance (GCR). GCR is a leading candidate mechanism linking psychosocial threat with systemic inflammation. Whereas cortisol released in response to threat normally binds to glucocorticoid receptors and down-regulates inflammation, chronic perceptions of threat lead to a state of GCR, in which glucocorticoid receptors become insensitive to the anti-inflammatory effects of circulating cortisol. Mindfulness training is proposed to diminish perceptions of threat in ways that restore glucocorticoid receptor sensitivity. To test this biological pathway, this study assesses functional GCR and biomarkers of inflammation before and after a Mindfulness-Based Stress Reduction (MBSR) or control Health Enhancement Program (HEP) in a sample of lonely older adults (N=188). Loneliness is a form of chronic psychosocial threat, and is consistently associated with GCR and systemic inflammation, yet MBSR is one of very few interventions successful in reducing loneliness. MBSR is expected to decrease GCR (and restore glucocorticoid receptor sensitivity) compared to HEP from pre- to post- intervention. Moreover, these decreases in GCR are expected to mediate the effects of MBSR (vs. HEP) on lowering systemic inflammation (CRP and IL-6) from pre-intervention to 3-month follow-up. In sum, this proposal investigates decreased GCR as a biological mechanism through which mindfulness training reduces inflammatory disease risk. It addresses NCCIH's call for research on understanding the biological mechanisms of action underlying mind-body intervention approaches and complements NCCIH's special interest in alleviating inflammatory processes. The knowledge gained from this research will contribute to a better understanding of the basic biological pathways underlying mindfulness practices, which may help to identify and target populations likely to benefit from mindfulness training. The research and training plan described in this application provide opportunities for the applicant to develop a knowledge base and methodology in psychoneuroimmunology, learn statistical techniques for analyzing complex mechanistic pathways, and develop the professional skills necessary for a successful career testing biological and psychological mechanisms underlying mind-body interventions.